For amides

FS(0)20CH3. Colourless liquid, b.p. 94°C. Functions as a powerful methylating agent, even for amides and nitriles which are not attacked by conventional alkylating agents like dialkyl sulphates. 

Amides. Names for amides are derived from the names of the acid radicals (or from the names of acids by replacing acid by amide) for example, S02(NH2)2, sulfonyl diamide (or sulfuric diamide) NH2SO3H, sulfamidic acid (or amidosulfuric acid). 

Hydrolysis of esters and amides by enzymes that form acyl enzyme intermediates is similar in mechanism but different in rate-limiting steps. Whereas formation of the acyl enzyme intermediate is a rate-limiting step for amide hydrolysis, it is the deacylation step that determines the rate of ester hydrolysis. This difference allows elimination of the undesirable amidase activity that is responsible for secondary hydrolysis without affecting the rate of synthesis. Addition of an appropriate cosolvent such as acetonitrile, DMF, or dioxane can selectively eliminate undesirable amidase activity (128). 

Reactions with strongly basic nucleophiles such as potassium amide in liquid ammonia may prove much more complex than direct substitution. 2-Chloro-4,6,7-triphenylpteridine reacts under these conditions via an S ANRORC mechanism to form 2-amino-4,6,7-triphenylpteridine and the dechlorinated analogue (78TL2021). The attack of the nucleophile exclusively at C-4 is thereby in good accord with the general observation that the presence of a chloro substituent on a carbon position adjacent to a ring nitrogen activates the position meta to the chlorine atom for amide attack. 

Protection of the amide — NH is an area of protective group chemistiy that has received little attention, and as a consequence few methods exist for amide — NH protection. Most of the cases found in the literature do not represent protective groups in the true sense, in that the protective group is often incoiporated as a handle to introduce nitrogen into a molecule rather than installed to protect a nitrogen which at some later time is deblocked. For this reason many of the following examples deal primarily with removal rather than with both formation and cleavage. 

WF Jorgensen, CJ Swenson. Optimized mtermolecular potential functions for amides and peptides. Stnicture and properties of liquid amides. J Am Chem Soc 107 569-578, 1985. 

On the basis of the general mechanism for amide hydrolysis in acidic solution shown in Figure 20.7, write an analogous sequence of steps for the... 

Ho, the acidity function introduced by Hammett, is a measure of the ability of the solvent to transfer a proton to a base of neutral charge. In dilute aqueous solution ho becomes equal to t d Hq is equal to pH, but in strongly acid solutions Hq will differ from both pH and — log ch+. The determination of Ho is accomplished with the aid of Eq. (8-89) and a series of neutral indicator bases (the nitroanilines in Table 8-18) whose pA bh+ values have been measured by the overlap method. Table 8-19 lists Ho values for some aqueous solutions of common mineral acids. Analogous acidity functions have been defined for bases of other structural and charge types, such as // for amides and Hf for bases that ionize with the production of a carbocation ... 

Dicyclohexylcarbodiimide is a solid material, the Lewis structure for which resembles that of ketene. The molecule is a widely used catalyst for amide synthesis and other dehydration reactions. 

Rotational barriers for bonds which have partly double bond character are significantly too low. This is especially a problem for the rotation around the C-N bond in amides, where values of 5-10 kcal/mol are obtained. A purely ad hoc fix has been made for amides by adding a force field rotational term to the C-N bond which raises the value to 20-25 kcal/mol, and brings it in line with experimental data. Similarly, the barrier for rotation around the central bond in butadiene is calculated to be only 0.5-2.0 kcal/mol, in contrast to the experimental value of 5.9 kcal/mol. 

This tendency is especially significant in compounds containing functional groups capable of addition with the formation of both five- and six-membered rings. It has been shown that for amides and hydrazides of azolecarboxylic acids, selectively, and for the acids with any arrangement of a function and triple bond, heterocyclization always leads to the closure of the six-membered ring. Similar reactions in the benzoic series mainly lead to the formation of five-membered rings. 

Conversion of Amides into Carboxylic Acids Hydrolysis Amides undergo hydrolysis to yield carboxylic acids plus ammonia or an amine on heating in either aqueous acid or aqueous base. The conditions required for amide hydrolysis are more severe than those required for the hydrolysis of add chlorides or esters but the mechanisms are similar. Acidic hydrolysis reaction occurs by nucleophilic addition of water to the protonated amide, followed by transfer of a proton from oxygen to nitrogen to make the nitrogen a better leaving group and subsequent elimination. The steps are reversible, with the equilibrium shifted toward product by protonation of NH3 in the final step. 

Conversion of Amides into Amines Reduction Like other carboxylic acid derivatives, amides can be reduced by LiAlH.4. The product of the reduction, however, is an amine rather than an alcohol. The net effect of an amide reduction reaction is thus the conversion of the amide carbonyl group into a methylene group (C=0 —> CTbV This kind of reaction is specific for amides and does not occur with other carboxylic acid derivatives. 

The method outlined here works well for amides of primary carbinamines. For amides of secondary carbinamines, lower temperatures must be used, and solvents such as methylene chloride are used in place of the acetic acid (the amide need not be completely soluble in the solvent) the procedure of White and Aufdermarsh6 used for a trimethylacetamide is recommended in such a case. Nitrosoamides of tertiary carbinamines are very unstable, and the salt method of preparation is suggested for these compounds 6... 

For amide enolates (X = NR2), with Z geometry, model transition state D is intrinsically favored, but, again, large X substituents favor the formation of nt/-adducts via C. Factors that influence the diastereoselectivity include the solvent, the enolate counterion and the substituent pattern of enolate and enonc. In some cases either syn- or unh-products are obtained preferentially by varying the nature of the solvent, donor atom (enolate versus thioeno-late), or counterion. Most Michael additions listed in this section have not been examined systematically in terms of diastereoselectivity and coherent transition stale models are currently not available. Similar models to those shown in A-D can be used, however all the previously mentioned factors (among others) may be critical to the stereochemical outcome of the reaction. 

POTENTIAL SURFACES FOR AMIDE HYDROLYSIS IN SOLUTION AND IN SERINE PROTEASES... 

Potential functions induced-dipole terms, 84-85 minimization, 113-116 nonbonded interactions, 84-85 Potential of mean force, 43, 144 Potential surfaces, 1,6-11, 85, 87-88, 85 for amide hydrolysis, 176-181,178,179, 217-220, 218... 

Reactive trajectories, 43-44,45, 88,90-92,215 downhill trajectories, 90,91 velocity of, 90 Relaxation processes, 122 Relaxation times, 122 Reorganization energy, 92,227 Resonance integral, 10 Resonance structures, 58,143 for amide hydrolysis, 174,175 covalent bonding arrangement for, 84 for Cys-His proton transfer in papain, 141 for general acid catalysis, 160,161 for phosphodiester hydrolysis, 191-195,... 

Potential Surfaces for Amide Hydrolysis in Solution and in Serine Proteases, 173... 

From a medicinal chemist s point of view, oxadiazoles are among the most important heterocycles as they are one of the most commonly used bioisosters for amide and ester groups [67]. As such it is hardly surprising that the two regioisomeric oxadiazole scaffolds received the most interest in the field of microwave-assisted synthesis using polymer-supported reagents. 

For amide hydrolysis in base, the initial adduct would revert to starting materials (without remarkable stabilization, an amide ion is a hopeless leaving group, so that path b does not compete with path a), bnt a not very difflcnlt proton transfer gives an intermediate in which the amine is the better leaving gronp and path b can compete with path a. ... 

For amide hydrolysis in acid, proton transfer to give a cationic intermediate is easy, and breakdown to products is favored over reversion to starting material process b is hopelessly bad, but process b is better than a. 

Another useful reagent for amide formation is compound 1, known as BOP-C1,141 which also proceeds by formation of a mixed carboxylic phosphoric anhydride. 

It has been found that a number of bidentate ligands greatly expand the scope of copper catalysis. Copper(I) iodide used in conjunction with a chelating diamine is a good catalyst for amidation of aryl bromides. Of several diamines that were examined, rra s-yV,yV -dimethylcyclohexane-l,2-diamine was among the best. These conditions are applicable to aryl bromides and iodides with either ERG or EWG substituents, as well as to relatively hindered halides. The nucleophiles that are reactive under these conditions include acyclic and cyclic amides.149... 

We have, therefore, taken a different approach (10). In a copolymer of acrylamide with acrylic acid, tEe initial rate constant for amide hydrolysis is given by... 

The UV-spectra of azolides have already been discussed in the context of hydrolysis kinetics in Chapter 1. Specific infrared absorptions of azolides were mentioned there as well increased reactivity of azolides in nucleophilic reactions involving the carbonyl group is paralleled by a marked shift in the infrared absorption of the corresponding carbonyl bond toward shorter wavelength. For example, for the highly reactive N-acetyl-tetrazole this absorption is found in a frequency range (1780 cm-1) that is very unusual for amides obviously the effect is due to electron attraction by the heterocyclic sys-tem.[40] As mentioned previously in the context of hydrolysis kinetics of both imidazo-... 

Golczak, M, Imanishi, Y, Kuksa, V, Maeda, T, Kubota, R, and Palczewski, K, 2005a. Lecithin Retinol acyltransferase is responsible for amidation of retinylamine, a potent inhibitor of the retinoid cycle. J Biol Chem 280, 42263 12273. 

The recombinantly expressed nitrilase from Pseudomonas fluorescens EBC 191 (PFNLase) was applied in a study aimed at understanding the selectivity for amide versus acid formation from a series of substituted 2-phenylacetonitriles, including a-methyl, a-chloro, a-hydroxy and a-acetoxy derivatives. Amide formation increased when the a-substituent was electron deficient and was also affected by chirality of the a- stereogenic center for example, 2-chloro-2-phenylacetonitrile afforded 89% amide while mandelonitrile afforded 11% amide from the (R)-enantiomer but 55% amide was formed from the (5)-enantiomer. Relative amounts of amide and carboxylic acid was also subject to pH and temperature effects [87,88]. 

Warshel, Levitt, and Lifson derived a partially optimised consistent force field for amides and lactams (25). It is composed of an alkane part and an amide-part. The former was taken over from analogous earlier calculations for saturated hydrocarbons (17). The potential constants of the amide-part were optimised with the help of a large number of experimental frequencies (taken from TV-methylform amide, acetamide, iV-methylacetamide, and several deuterated species) as well as experimental geometry data for 7V-methylacet-amide. The resulting force field was used for the calculation of vibrational and conformational properties of 2-pyrrolidone, 2-piperidone and e-caprolactam. 

In a detailed investigation, Turner and coworkers have described the preparation and application of solid-supported cyclohexane-1,3-dione as a so-called capture and release reagent for amide synthesis, as well as its use as a novel scavenger resin [125]. Their report included a three-step synthesis of polymer-bound cyclohexane-1,3-dione (CHD resin, Scheme 7.104) from inexpensive and readily available starting materials. The key step in this reaction was microwave-assisted complete hydrolysis of 3-methoxy-cyclohexen-l-one resin to the desired CHD resin. 

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